Personal care compositions with glutathione precursor comprising 4-substituted resorcinols and amino acids

ABSTRACT

Topical personal care compositions containing amino acids and 4-substituted resorcinols for potentiating glutathione synthesis within skin cells. The compositions can be used to improve skin appearance of chronological aging or photoaging, resulting from exposure to UV light/sunlight, or environmental pollutants. The compositions are also useful for attaining even skin color and reducing pigmentation, age spots and discoloration.

FIELD OF THE INVENTION

The invention relates to topical personal care compositions containingingredients which increase glutathione production within skin cells.

BACKGROUND OF THE INVENTION

Glutathione (GSH) is a tripeptide that consists of glutamate, cysteine,and glycine. It is present in all mammalian tissues. It is the mainanti-oxidant in the living body: it protects cells from oxidation byquenching reactive oxygen species. GSH is believed to play a significantrole in protecting cells against the cytotoxic effects of ionizingradiation, heat, certain chemicals, and significantly, solar UVradiation (Tyrell et al., Photochem. Photobiol. 47: 405-412, 1988;Meister, J. Biol. Chem. 263: 205-217, 1988; Meister, Science200:471-477, 1985). While true in all areas of the body, this isparticularly important in the skin, which is so greatly exposed to thedamaging effects of radiation, particularly UV radiation, andenvironmental pollutants. Decrease in the intracellular concentration ofglutathione in skin is associated with cell damage, inflammation, skindarkening, discoloration, spots or freckles caused by exposure toultraviolet radiation, physiological aging, and the like. It is,therefore, highly desirable to enhance the generation of glutathione inskin.

A logical approach would seem to be to provide cells with an exogenoussource of GSH (e.g. through ingestion or topical delivery).Unfortunately, GSH is not bioavailable when administered exogenously,i.e. where localized extracellularly, it is broken down into itsconstituent amino acids (glutamate, cysteine, and glycine) for cellularuptake and synthesis of the GSH tripeptide. Thus, GSH is not directlytransported into the cells and therefore does not itself result in anintracellular increase of glutathione. Biosynthesis of GSH occurs in thecell in a tightly regulated manner. The quantity of glutathione in cellsdepends to a large degree on the availability of cysteine in the cells.Cysteine, a composite amino acid of GSH, may increase cellular levels ofGSH, but exposed sulfhydryl group of cysteine renders it unstable andreactive and also causes strong unpleasant odor. Unlike cysteine,cystine can be administered safely; cystine is transported into the celland converted to cysteine within the cell, the cysteine then beingavailable for intracellular GSH production

Topical compositions containing various amino acids and other skin careactives have been described, see e.g. Tanojo U.S. Pat. No. 7,300,649B,Laboratoire Filorga product, Schlachter WO 00/03689, Ermolin et al.US2011183040, Garlen et al. U.S. Pat. No. 4,707,354, Muller et al. U.S.Pat. No. 8,361,446, Hermann et al. U.S. Pat. No. 8,241,681. Compositionsfor potentiating intracellular glutathione production have beendescribed. See e.g. Chiba et al. U.S. Pat. No. 7,740,831, Crum et al(USRE37934, USRE42645, WO2016/033183, and US20050271726); Mammone U.S.Pat. No. 6,149,925, and Perricone US 20060063718.

Cystine is normally derived from the diet. Delivery of cystine fromtopical compositions, however, is challenging due to its extremely lowsolubility in biologically acceptable vehicle in a neutral pH range,which is the pH range required for topical application. The solubilityof cystine in water is 0.112 mg/ml at 25° C.; cystine is more soluble inaqueous solutions with pH less than 2 or pH above 8.

The present invention is based in part on a surprising finding that acombination of cystine with a specific class of resorcinols achieves asynergistic increase in intracellular glutathione levels, thuscounter-acting the drawback of cystine's low solubility at neutral pH.Furthermore, by virtue of including the resorcinol, only 2 out of the 3amino acids are sufficient to attain synergistic increase inintracellular production of glutathione.

SUMMARY OF THE INVENTION

In one embodiment, a personal care composition according to theinvention comprises:

-   a. glutathione precursor comprising, by weight of the composition:    -   i. from about 0.001% to about 2% of cystine;    -   ii. from about 0.01 to about 10% of a glutamate source; and    -   iii. from about 0.001 to about 3% of a resorcinol of Formula I:

wherein R is an ethyl group optionally substituted with a phenyl orsubstituted phenyl group or a straight or branched C3 to C16 alkyl groupoptionally substituted with a phenyl group or substituted phenyl group;and

-   b. a cosmetically acceptable carrier;-   c. wherein the pH of the composition is in the range of from about    3.5 to about 8.5.    In one embodiment, the topical cosmetic skin composition is a    leave-on composition, especially a leave-on non-solid composition.

In one embodiment, the present invention provides a method of improvingskin appearance, comprising applying the personal care composition tothe skin.

In one embodiment, the present invention provides a method of attainingeven skin color and reducing pigmentation, age spots and discoloration,comprising applying the composition to skin.

The compositions of the invention enhance the synthesis of glutathionein skin cells, and therefore, can be used to improve skin appearance ofchronological aging or photoaging, resulting from exposure to UVlight/sunlight, or environmental pollutants. A preferred method ofobtaining the benefits of the composition is via regular/chronic topicalapplication of the composition, to prevent development of skin damagewhich may result from even routine exposure to UV light or otherenvironmental insults which generate reactive oxygen species.

DETAILED DESCRIPTION OF THE INVENTION

Throughout the specification and claims, the following terms take themeanings explicitly associated herein, unless the context clearlydictates otherwise.

The phrases “in one embodiment” and “in some embodiments” as used hereindo not necessarily refer to the same embodiment(s), though it may.Furthermore, the phrases “in another embodiment” and “in some otherembodiments” as used herein do not necessarily refer to a differentembodiment, although it may. Thus, as described below, variousembodiments of the invention may be readily combined, without departingfrom the scope or spirit of the invention. In addition, each of theexamples given in connection with the various embodiments of theinvention which are intended to be illustrative, and not restrictive.

Except in the examples, or where otherwise explicitly indicated, allnumbers in this description indicating amounts of material or conditionsof reaction, physical properties of materials and/or use are to beunderstood as modified by the word “about.” All amounts are by weight ofthe final composition, unless otherwise specified. The disclosure of theinvention as found herein is to be considered to cover all embodimentsas found in the claims as being multiply dependent upon each otherirrespective of the fact that claims may be found without multipledependency or redundancy. In specifying any range of concentration oramount, any particular upper concentration can be associated with anyparticular lower concentration or amount.

“Comprising” is intended to mean “including” but not necessarily“consisting of” or “composed of.” In other words, the listed steps oroptions need not be exhaustive.

“Skin” is meant to include skin on the face, neck, chest, back, arms(including underarms), hands, legs, buttocks and scalp.

“Leave-on composition” refers to a composition that is applied to theskin and is not intended to be washed or rinsed off for some period oftime, specifically hours, as contrasted with skin cleansing or wash-offor rinse-off compositions which are rinsed off or washed off immediatelyor minutes after the application.

“Non-solid” with respect to the composition means that the compositionhas a measurable viscosity (measurable for instance with a BrookfieldViscometer DV-I+ (20RPM, RV6, 30 Seconds, 20° C.) in the range of from 1Pas to 500 Pas, preferably from 2 Pas to 100 Pas, more preferably from 3Pas to 50 Pas.

“Personal care composition” refers to any product applied to a humanbody for improving appearance, sun protection, cleansing, odor control,moisturization or general aesthetics. Non-limiting examples of personalcare compositions include skin lotions, creams, gels, lotions, facialmasks, sticks, shampoos, conditioners, shower gels, toilet bars,antiperspirants, deodorants, shave creams, depilatories, lipsticks,foundations, mascara, sunless tanners and sunscreen lotions.

“Skin cosmetic composition” refers to any product applied to a humanbody for improving appearance, sun protection, reducing wrinkledappearance or other signs of photoaging, odor control, skin lightening,even skin tone, or general aesthetics. Non-limiting examples of topicalcosmetic skin compositions include skin lotions, creams, facial masks,gels, sticks, antiperspirants, deodorants, lipsticks, foundations,mascara, liquid or gel body washes, soap bars, sunless tanners andsunscreen lotions.

Personal care composition of the present technology is preferably aleave-on non-solid skin cosmetic composition, because such compositionsare the most challenging in terms of incorporating cystine due to itslow solubility.

Glutathione (“GSH”) Precursor

The GSH precursor according to the present invention comprises aminoacids (glutamate and cystine and, optionally, glycine) and a4-substituted resorcinol. In one embodiment, the amino acids in the GSHprecursor are cystine and glutamate source. In one embodiment, the aminoacids in the GSH precursor are cystine and glutamate source and glycine.

Amino acids included in the inventive composition are present as Lstereo isomers, since this is the most abundant and natural isomericform found in nature. Since the building blocks of naturally-occurringproteins found in human skin, hair and nails are amino acids with the Lisomeric form, it is expected that L stereo isomer amino acids containedwithin personal care products of the present invention can have agreater interaction with these proteins that is intrinsically morebiocompatible in nature compared to the D stereo isomeric form. Inaddition, commercial production and supply of L stereo isomer aminoacids is significantly higher compared to the D stereo isomeric form.Finally, L stereo isomer amino acids are also more cost effective toproduce, more sustainable, more eco-friendly and available at a lowercost compared to D stereo isomer amino acids.

Any of the amino acids included in the present invention may be in theform of a salt, ester, or a salt thereof and the term “cystine,”“glutamate source”, and “glycine” used in the present specification alsoencompasses salts, esters, and salts of such esters. The salt, ester,and salt of such ester is not particularly limited as long as it isacceptable for topical application. For example, salts with inorganicacid or organic acid or anionic surfactants can be mentioned. As theinorganic acid, for example, hydrochloric acid, hydrobromic acid, nitricacid, sulfuric acid, phosphoric acid and the like can be mentioned, andas the organic acid C1-C18 linear, branched or cyclic, saturated orunsaturated, unsubstituted or substituted with heteroatoms, for exampleformic acid, acetic acid, trifluoroacetic acid, propionic acid, lacticacid, tartaric acid, oxalic acid, fumaric acid, succinic acid, maleicacid, citric acid, malonic acid, methanesulfonic acid, stearic acid,oleic acid, 12-hydroxystearic acid, ricinoleic acid, and the like can bementioned.

As the salt with a base, for example, alkali metal salts such as sodiumsalt, potassium salt and the like, alkaline earth metal salts such ascalcium salt, magnesium salt and the like, and the like can bementioned.

Esters of amino acids are typically C₁-C₈ esters or salts thereof, or inthe alternative C₁-C₅ esters, or in the alternative C₁-C₃ esters. Suchesters may be straight or branched or cyclic. Especially esters ofcystine are beneficial, due to their increased solubility, compared tocystine. Methyl and ethyl esters of cystine or salts thereof are mostpreferred, due to their efficacy to boost glutathione production andprovide antioxidant activity. When salts of esters are used, the samesalts are suitable as listed above.

Glutamate source can be present in the form of its functionalequivalents—glutamine, glutamic acid and/or pyroglutamic acid and/ortheir salts may be employed. Pyroglutamic acid (and/or salts thereof) ispreferred since it is more stable than glutamine or glutamic acid. Inone embodiment, amino acids in GSH precursor are cystine andpyroglutamic acid (and/or salts thereof). In one embodiment, amino acidsin GSH precursor are cystine and pyroglutamic acid and glycine (and/orsalts thereof).

4-substituted Resorcinol of Formula I

wherein R is an ethyl group optionally substituted with a phenyl orsubstituted phenyl group or C3 to C16 straight or branched alkyl groupoptionally substituted with a phenyl or substituted phenyl group, is acomponent of GSH precursor included in the invention. It has been foundthat by virtue of including amino acids and resorcinol described hereinglutathione production is synergistically increased, thus overcoming thedrawback of cystine's limited solubility. Furthermore, by virtue ofincluding the resorcinol, only 2 out of the 3 amino acids are sufficientto attain synergistic increase in intracellular production ofglutathione.

Resorcinol derivatives of formula (I) are preferably the compoundsselected from the group consisting of 4-ethylresorcinol,4-propylresorcinol, 4-isopropylresorcinol, 4-butylresorcinol,4-pentylresorcinol, 4-hexylresorcinol, 4-heptylresorcinol, 4-octylresorcinol, 4-nonylresorcinol, 4-decylresorcinol, 4-dodecylresorcinol,4-(1-methylpropyl)resorcinol, 4-(1-ethylpropyl)resorcinol,4-(1-phenylethyl)resorcinol, 4-(2-phenylethyl)resorcinol,4-(1-phenylpropyl)resorcinol, 4-(2-phenyl propyl) resorcinol,4-(3-phenylpropyl)resorcinol, 4-(1-phenylbutyl)resorcinol,4-(2-phenylbutyl)resorcinol, 4-(3-phenylbutyl)resorcinol,4-(4-phenylbutyl)resorcinol, 4-(1-phenylhexyl)resorcinol,4-(2-phenylhexyl)resorcinol, 4-[1-(2-methylphenyl)ethyl]resorcinol,4-[1-(3-methylphenyl)ethyl]resorcinol,4-[1-(4-methylpheny)ethyl]resorcinol,4-[2-(2-methylphenyl)ethyl]resorcinol,4-[2-(3-methylphenyl)ethyl]resorcinol,4-[2-(4-methylphenyl)ethyl]resorcinol,4-[1-(4-methylphenyl)propyl]resorcinol,4-[1-(4-methylphenyl)butyl]resorcinol,4-[1-(4-methylphenyl)hexyl]resorcinol,4-[1-(2-methoxyphenyl)ethyl]resorcinol,4-[1-(3-methoxyphenyl)ethyl]resorcinol,4-[1-(4-methoxyphenyl)ethyl]resorcinol,4-[2-(2-methoxyphenyl)ethyl]resorcinol,4-[2-(3-methoxyphenyl)ethyl]resorcinol,4-[2-(4-methoxyphenyl)ethyl]resorcinol,4-[1-(4-methoxyphenyl)propyl]resorcinol,4-[1-(4-methoxyphenyl)butyl]resorcinol,4-[1-(4-methoxyphenyl)hexyl]resorcinol,4-[1-(3,4-dimethylphenyl)ethyl]resorcinol,4-[1-(3,4-dimethoxyphenyl)ethyl]resorcinol,4-[2-(3,4-dimethylphenyl)ethyl]resorcinol,4-[2-(3,4-dimethoxyphenyl)ethyl]resorcinol,4-[1-(3-methoxy-4-methylphenyl)ethyl]resorcinol,4-[2-(3-methoxy-4-methylphenyl)ethyl]resorcinol,4-[1-(3-methyl-4-methoxyphenyl)ethyl]resorcinol,4-[2-(3-methyl-4-methoxyphenyl)ethyl]resorcinol,4-[1-(3-methoxy-4-methylphenyl)propyl]resorcinol,4-[1-(3-methyl-4-methoxyphenyl)propyl]resorcinol,4-[1-(3-methoxy-4-methylphenyl)butyl]resorcinol,4-[1-(3-methyl-4-methoxyphenyl)butyl]resorcinol,4-[1-(3-methoxy-4-methylphenyl)hexyl]resorcinol,4-[1-(3-methyl-4-methoxyphenyl)hexyl]resorcinol,4-[1-(3,5-dimethoxy-4-methylphenyl)ethyl]resorcinol,4-[2-(3,5-dimethoxy-4-methylphenyl)ethyl]resorcinol,4-[1-(3,5-dimethoxy-4-methylphenyl)propyl]resorcinol,4-[1-(3,5-dimethoxy-4-methylphenyl)butyl]resorcinol,4-[1-(3,5-dimethoxy-4-methylphenyl)hexyl]resorcinol,4-[1-(3,4,5-trimethoxyphenyl)ethyl]resorcinol,4-[2-(3,4,5-trimethoxyphenyl)ethyl]resorcinol,4-[1-(3,4,5-trimethoxyphenyl)propyl]resorcinol,4-[1-(3,4,5-trimethoxyphenyl)butyl]resorcinol, 4-[1-(3,4,5-trimethoxyphenyl)hexyl]resorcinol and their mixtures. Thepreferred resorcinols are 4-hexylresorcinol, 4-ethylresorcinol,4-isopropylresorcinol, 4-butylresorcinol, and4-(1-phenylethyl)resorcinol.

In one embodiment, the composition of the invention is a leave-onnon-solid composition in the form of a personal care topical emulsion,lotion, gel, cream, or vanishing cream comprising glutathione precursorwhich comprises cystine, glutamate (especially pyroglutamic acid or saltthereof, e.g. sodium pyroglutamate) and one or more of4-hexylresorcinol, 4-ethylresorcinol, 4-isopropylresorcinol,4-butylresorcinol, and 4-(1-phenylethyl)resorcinol, at pH of 3.5 to 8.5.

In one embodiment, the composition of the invention is a leave-onnon-solid composition in the form of a personal care topical emulsion,lotion, gel, cream, or vanishing cream comprising glutathione precursorwhich comprises cystine, glutamate (especially pyroglutamic acid or saltthereof, e.g. sodium pyroglutamate), glycine, and 4-hexylresorcinol atpH of 3.5 to 8.5, especially at pH of 5 to 8.

In one embodiment, the composition of the invention is a leave-onnon-solid composition in the form of a personal care topical emulsion,lotion, gel, cream, or vanishing cream comprising glutathione precursorwhich comprises cystine, glutamate (especially pyroglutamic acid or saltthereof, e.g. sodium pyroglutamate), glycine, and 4-butylresorcinol atpH of 3.5 to 8.5, especially at pH of 5 to 8.

In one embodiment, the composition of the invention is a leave-onnon-solid composition in the form of a personal care topical emulsion,lotion, gel, cream, or vanishing cream comprising glutathione precursorwhich comprises cystine, glutamate (especially pyroglutamic acid or saltthereof, e.g. sodium pyroglutamate), glycine and4-(1-phenylethyl)resorcinol at pH of 3.5 to 8.5, especially at pH of 5to 8.

Amounts

In one embodiment, cystine is included in an amount of from 0.001 to 2%,or in the alternative of from to 0.005 to 1%, or from 0.008 to 0.5%, orin the alternative from 0.008 to 0.4%. In one embodiment, glutamatesource (preferably pyroglutamate) is included in an amount of from 0.01to 10%, or in the alternative of from to 0.01 to 5%, or from 0.05 to 1%,or in the alternative from 0.05 to 0.5%. In one embodiment, glycinesource is included in an amount of from 0.01 to 10%, or in thealternative of from to 0.01 to 5%, or from 0.01 to 1%, or in thealternative from 0.01 to 0.2%, or in the alternative from 0.01 to 0.1%.In one embodiment, resorcinol is included in an amount of from 0.001% to3%, or in the alternative of from to 0.01 to 2%, or from 0.05 to 1.5%,or in the alternative from 0.05 to 1.2%.

The total weight of amino acids is at least twice as much as the weightof the resorcinol. In one embodiment, the weight ratio of total aminoacids to resorcinol is in the range of from 3:1 to 15:1. In thealternative, the weight ratio of total amino acids to resorcinol is inthe range of from 2:1 to 15:1.

Carrier

Compositions of this invention also include a cosmetically acceptablecarrier. Amounts of the carrier may range from 1 to 99.9%, preferablyfrom 70 to 95%, optimally from 80 to 90%. Among the useful carriers arewater, emollients, fatty acids, fatty alcohols, thickeners andcombinations thereof. The carrier may be aqueous, anhydrous or anemulsion. Preferably the compositions are aqueous, especially water andoil emulsions of the water-in-oil or oil-in-water type or multipleemulsions of the water-in-oil-in-water or oil-in-water-in-oil variety.Water when present may be in amounts ranging from 5 to 95%, preferablyfrom about 20 to about 70%, optimally from 35 to 60% by weight.

Emollient materials may serve as cosmetically acceptable carriers. Thesemay be in the form of silicone oils, natural or synthetic esters,hydrocarbons, alcohols and fatty acids. Amounts of the emollients mayrange anywhere from 0.1 to 95%, preferably between 1 and 50% by weightof the composition.

Silicone oils may be divided into the volatile and nonvolatile variety.The term “volatile” as used herein refers to those materials which havea measurable vapor pressure at ambient temperature. Volatile siliconeoils are preferably chosen from cyclic (cyclomethicone) or linearpolydimethylsiloxanes containing from 3 to 9, preferably from 5 to 6,silicon atoms. Nonvolatile silicone oils useful as an emollient materialinclude polyalkyl siloxanes, polyalkylaryl siloxanes and polyethersiloxane copolymers. The essentially nonvolatile polyalkyl siloxanesuseful herein include, for example, polydimethyl siloxanes withviscosities of from 5×10⁻⁶ to 0.1 m²/s at 25° C. Among the preferrednonvolatile emollients useful in the present compositions are thepolydimethyl siloxanes having viscosities from 1×10⁻⁵ to about 4×10⁻⁴m²/s at 25° C. Another class of nonvolatile silicones are emulsifyingand non-emulsifying silicone elastomers. Representative of this categoryis Dimethicone/Vinyl Dimethicone Crosspolymer available as Dow Corning9040, General Electric SFE 839, and Shin-Etsu KSG-18. Silicone waxessuch as Silwax WS-L (Dimethicone Copolyol Laurate) may also be useful.

Among the ester emollients are:a) Alkyl esters of saturated fatty acids having 10 to 24 carbon atoms.Examples thereof include behenyl neopentanoate, isononyl isonanonoate,isopropyl myristate and octyl stearate.b) Ether-esters such as fatty acid esters of ethoxylated saturated fattyalcohols.c) Polyhydric alcohol esters. Ethylene glycol mono and di-fatty acidesters, diethylene glycol mono- and di-fatty acid esters, polyethyleneglycol (200-6000) mono- and di-fatty acid esters, propylene glycol mono-and di-fatty acid esters, polypropylene glycol 2000 monostearate,ethoxylated propylene glycol monostearate, glyceryl mono- and di-fattyacid esters, polyglycerol poly-fatty esters, ethoxylated glycerylmono-stearate, 1,3-butylene glycol monostearate, 1,3-butylene glycoldistearate, polyoxyethylene polyol fatty acid ester, sorbitan fatty acidesters, and polyoxyethylene sorbitan fatty acid esters are satisfactorypolyhydric alcohol esters. Particularly useful are pentaerythritol,trimethylolpropane and neopentyl glycol esters of C₁-C₃₀ alcohols.d) Wax esters such as beeswax, spermaceti wax and tribehenin wax.e) Sugar ester of fatty acids such as sucrose polybehenate and sucrosepolycottonseedate.

Natural ester emollients principally are based upon mono-, di- andtri-glycerides. Representative glycerides include sunflower seed oil,cottonseed oil, borage oil, borage seed oil, primrose oil, castor andhydrogenated castor oils, rice bran oil, soybean oil, olive oil,safflower oil, shea butter, jojoba oil and combinations thereof. Animalderived emollients are represented by lanolin oil and lanolinderivatives. Amounts of the natural esters may range from 0.1 to 20% byweight of the compositions.

Hydrocarbons which are suitable cosmetically acceptable carriers includepetrolatum, mineral oil, C₁₁-C₁₃ isoparaffins, polybutenes andespecially isohexadecane, available commercially as Permethyl 101A fromPresperse Inc.

Fatty acids having from 10 to 30 carbon atoms may also be suitable ascosmetically acceptable carriers. Illustrative of this category arepelargonic, lauric, myristic, palmitic, stearic, isostearic, oleic,linoleic, linolenic, hydroxystearic and behenic acids and mixturesthereof.

Fatty alcohols having from 10 to 30 carbon atoms are another usefulcategory of cosmetically acceptable carrier. Illustrative of thiscategory are stearyl alcohol, lauryl alcohol, myristyl alcohol, oleylalcohol and cetyl alcohol and mixtures thereof.

Thickeners or rheology modifiers can be utilized as part of thecosmetically acceptable carrier of compositions according to the presentinvention. Typical thickeners include crosslinked acrylates (e.g.Carbopol 982®), hydrophobically-modified acrylates (e.g. Carbopol1382®), polyacrylamides (e.g. Sepigel 305®), acryloylmethylpropanesulfonic acid/salt polymers and copolymers (e.g. Aristoflex HMB® andAVC®), cellulosic derivatives and natural gums. Among useful cellulosicderivatives are sodium carboxymethylcellulose, hydroxypropylmethocellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethylcellulose and hydroxymethyl cellulose. Natural gums suitable for thepresent invention include guar, xanthan, sclerotium, carrageenan, pectinand combinations of these gums. Inorganics may also be utilized asthickeners, particularly clays such as bentonites and hectorites, fumedsilicas, talc, calcium carbonate and silicates such as magnesiumaluminum silicate (Veegum®). Amounts of the thickener may range from0.0001 to 10%, usually from 0.001 to 1%, or from 0.01 to 0.5%.

Preferred are emollients that can be used, especially for productsintended to be applied to the face, to improve sensory properties andare chosen from the group of polypropylene glycol-14 butyl etherotherwise known as Tegosoft PBE, or PPG15 stearyl ether such as TegosoftE, other oils such as esters, specifically, isopropyl myristate,isopropyl palmitate, other oils could include castor oils andderivatives thereof.

Humectants of the polyhydric alcohol-type can be employed ascosmetically acceptable carriers. Typical polyhydric alcohols includeglycerol, polyalkylene glycols and more preferably alkylene polyols andtheir derivatives, including propylene glycol, dipropylene glycol,polypropylene glycol, polyethylene glycol and derivatives thereof,sorbitol, hydroxypropyl sorbitol, hexylene glycol, 1,3-butylene glycol,isoprene glycol, 1,2,6-hexanetriol, ethoxylated glycerol, propoxylatedglycerol and mixtures thereof. The amount of humectant may rangeanywhere from 0.5 to 50%, preferably between 1 and 15% by weight of thecomposition.

Skin moisturizers, e.g. hyaluronic acid and/or its precursor N-acetylglucosamine may be included. N-acetyl glucosamine may be found in sharkcartilage or shitake mushrooms and are available commercially fromMaypro Industries, Inc (New York). Other preferred moisturizing agentsinclude hydroxypropyl tri(C₁-C₃ alkyl)ammonium salts. These salts may beobtained in a variety of synthetic procedures, most particularly byhydrolysis of chlorohydroxypropyl tri(C₁-C₃ alkyl)ammonium salts. A mostpreferred species is 1,2-dihydroxypropyltrimonium chloride, wherein theC₁-C₃ alkyl is a methyl group. Amounts of the salt may range from 0.2 to30%, and preferably from 0.5 to 20%, optimally from 1% to 12% by weightof the topical composition, including all ranges subsumed therein.

Ordinarily the C₁-C₃ alkyl constituent on the quaternized ammonium groupwill be methyl, ethyl, n-propyl, isopropyl or hydroxyethyl and mixturesthereof. Particularly preferred is a trimethyl ammonium group knownthrough INCI nomenclature as a “trimonium” group. Any anion can be usedin the quat salt. The anion may be organic or inorganic with provisothat the material is cosmetically acceptable. Typical inorganic anionsare halides, sulfates, phosphates, nitrates and borates. Most preferredare the halides, especially chloride. Organic anionic counter ionsinclude methosulfate, toluoyl sulfate, acetate, citrate, tartrate,lactate, gluconate, and benzenesulfonate.

Still other preferred moisturizing agents which may be used, especiallyin conjunction with the aforementioned ammonium salts includesubstituted urea like hydroxymethyl urea, hydroxyethyl urea,hydroxypropyl urea; bis(hydroxymethyl) urea; bis(hydroxyethyl) urea;bis(hydroxypropyl) urea; N,N′-dihydroxymethyl urea; N,N′-di-hydroxyethylurea; N,N′-di-hydroxypropyl urea; N,N,N′-tri-hydroxyethyl urea;tetra(hydroxymethyl) urea; tetra(hydroxyethyl) urea; tetra(hydroxypropylurea; N-methyl, N′-hydroxyethyl urea; N-ethyl-N′-hydroxyethyl urea;N-hydroxypropyl-N′-hydroxyethyl urea and N,N′dimethyl-N-hydroxyethylurea. Where the term hydroypropyl appears, the meaning is generic foreither 3-hydroxy-n-propyl, 2-hydroxy-n-propyl, 3-hydroxy-i-propyl or2-hydroxy-i-propyl radicals. Most preferred is hydroxyethyl urea. Thelatter is available as a 50% aqueous liquid from the National Starch &Chemical Division of ICI under the trademark Hydrovance. Amounts ofsubstituted urea that may be used in the topical composition of thisinvention range from 0.01 to 20%, or from 0.5 to 15%, or from 2 to 10%.

When ammonium salt and substituted urea are used, in a most especiallypreferred embodiment at least from 0.01 to 25%, or from 0.2 to 20%, orfrom 1 to 15% humectant, like glycerine, is used. Further moisturizingagents for use herein include petrolatum and/or various aquaporinmanipulating actives and/or oat kernel flour.

pH of the Composition

In one embodiment, the pH of the personal care composition is between3.5 and 8.5. In some embodiments, the pH of the personal carecomposition is between pH 3.5 and pH 8. In some embodiments, the pH ofthe personal care composition is between pH 5 to pH 7.8. In someembodiments, the pH of the personal care composition is between 5 and7.5.

Preferred Optional Ingredients

In some embodiments, the personal care composition, and especially aleave-on skin cosmetic composition of the present invention containssun-screen. These are typically a combination of organic and inorganicsunscreens. It is particularly important to include both UV-A and UV-Bradiation sunscreens.

UV-B sunscreen oil may be selected from the class of cinnamic acid,salicylic acid, diphenyl acrylic acid, or derivatives thereof. The UV-Bsunscreen oil may include one or more of octyl salicylate,3,3,5-trimethylcyclohexyl 2-hydroxybenzoate, ethylhexyl salicylate,2-ethylhexyl 2-cyano-3,3-diphenyl-2-propenoate, or2-ethylhexyl-4-methoxycinnamate (also known as octyl methoxycinnamate or“OMC”). Such UV-B sunscreen oils are typically commercially available,such as Octisalate™ (octyl salicylate), Homosalate™(3,3,5-trimethyleyclohexyl 2-hydroxybenzoate), NeoHeliopan™ (a range oforganic UV filters including OMC (Neo Heliopan AV™) and ethylhexylsalicylate (Neo Heliopan OS™)), Octocrylene™ and Milestab 3039™(2-ethylhexyl-2-cyano-3,3-diphenyl-2-propenoate) or Parsol MCX™(2-ethylhexyl-4-methoxycinnamate). The amount of UV-B sunscreen oil inthe personal care composition may be 0.1 wt % to 20 wt %, or 0.2 wt % to10 wt %, or 0.5 wt % to 7 wt %, or 2 wt % to 6 wt %.

The personal care composition may further include a UV-B sunscreen thatis water-soluble. The water soluble UV-B sunscreen may also includephenylbezimidazole sulfonic acid (also known as ensulizole),4-aminobenzoic acid (also known as para-aminobenzoic acid or “PABA”), orboth.

The personal care composition of any one of the above embodiments mayfurther include 0.1 wt % to 10 wt % of a UV-A sunscreen oil. The UV-Asunscreen oil may include one or more of4-t-butyl-4′-methoxydibenzoylmethane (“avobenzone”),2-methyldibenzoylmethane, 4-methyl-dibenzoyl-ethane,4-isopropyldibenzoyl-methane, 4-tert-butyldibenzoylmethane,2,4-dimethyldibenzoylmethane, 2,5-dimethyldibenzoylmethane,4,4′-diisopropyldibenzoylmethane,2-methyl-5-isopropyl-4′-methoxy-dibenzoylmethane,2-methyl-5-tert-butyl-4′-methoxy-dibenzoyl methane,2,4-dimethyl-4′-methoxydibenzoylmethane,2,6-dimethyl-4-tert-butyl-4′methoxy-dibenzoylmethane,diethylaminohydroxybenzoyl hexyl benzoate, ecamsule, or methylanthranilate. The amount of UV-A sunscreen oil in the personal carecomposition may be 0.5 wt % to 7 wt %, or 1 wt % to 5 wt %.

Additional suitable sunscreen oils suitable for use in the personal carecomposition include those commercially available from BASF corporation:Uvinul T-150 (Ethylhexyl triazone; a UV-B sunscreen oil), Uvinul A Plus(Diethylamino hydroxybenzoyl hexyl benzoate; a UV-A sunscreen oil),Tinosorb S (bis-ethylhexyloxyphenol methoxyphenyl triazine; a UV-A andUV-B sunscreen oil), Tinosorb M(methylene bisbenzotriazolyltetramethylbutylphenol; a UV-A and UV-B sunscreen oil). Bisdisulizonedisodium may also be included in the personal care composition.

A particularly preferred combination of UV-A and UV-B sunscreen oils isavobenzone and 2-ethylhexyl-4-methoxycinnamate.

In some embodiments, the sunscreen is an inorganic sunscreen. Examplesof inorganic sunscreens suitable for use in the skin care composition ofthe present invention include, but are not limited to, microfinetitanium dioxide, zinc oxide, polyethylene and various other polymers.By the term “microfine” is meant particles of average size ranging from10 to 200 nm, alternatively from 20 to 100 nm. Amounts of the sunscreenwhen present in a skin care formulation according to some embodiments ofthe present invention may range from 0.1% to 30%, alternatively from 2%to 20%, alternatively from 4% to 10%.

It has been taught that selenium source, e.g. selenomethionine, is anessential ingredient, along with constituent amino acids of GSH, forenabling GSH intracellular biosynthesis; the transsulfuration pathway(also called the cystathionine pathway) allows the utilization ofmethionine for GSH synthesis Surprisingly, it has been found as part ofthe present invention, however, that a selenium source is not necessary,and is indeed superfluous, to achieve intracellular increase in GSHcontent according to the present invention. Although selenium source maybe included, it is preferably avoided in topical skin care compositionsof the invention because it is considered a skin sensitizer under someregulatory regimes. Accordingly, the amount of selenium in the presentcompositions is from 0 to maximum 0.1%, or at most 0.05%, optimally nomore than 0.01%.

The inventive composition preferably includes a skin lighteningcompound, in addition to resorcinols included herein, to obtain optimumskin lightening performance at an optimum cost. Illustrative substancesare additional resorcinols (2,5-disubstituted, 4,5-disubstituted, and4,6 di-substituted), placental extract, lactic acid, niacinamide,arbutin, kojic acid, ferulic acid, hydroquinone, resorcinol derivativesincluding di-substituted resorcinols and combinations thereof. Morepreferably, such skin lightening compound is a tyrosinase inhibitor,most preferably a compound selected from the group consisting of kojicacid, hydroquinone and other (non-4 substituted resorcinols). Also,dicarboxylic acids represented by the formula HOOC—(CxHy)—COOH where x=4to 20 and y=6 to 40 such as azelaic acid, sebacic acid, oxalic acid,succinic acid, fumaric acid, octadecenedioic acid (e.g. Arlatone DC) ortheir salts or a mixture thereof, most preferably fumaric acid or saltthereof, especially di-sodium salt. It has been found that combinationwith 12 HSA with fumaric acid or salts thereof are particularlypreferred, especially for skin lightening formulations. Amounts of theseagents may range from 0.1 to 10%, preferably from 0.5 to 2%. It ispreferred that the skin lightening coactive according to the inventionis vitamin 83 or a derivative thereof and is selected from the groupconsisting of niacinamide, nicotinic acid esters, non-vasodilatingesters of nicotinic acid, nicotinyl amino acids, nicotinyl alcoholesters of carboxylic acids, nicotinic acid N-oxide, niacinamide N-oxideand mixtures thereof.

Another preferred ingredient of the inventive compositions is aretinoid. As used herein, “retinoid” includes all natural and/orsynthetic analogs of Vitamin A or retinol-like compounds which possessthe biological activity of Vitamin A in the skin as well as thegeometric isomers and stereoisomers of these compounds. The retinoid ispreferably retinol, retinol esters (e.g., C₂-C₂₂ alkyl esters ofretinol, including retinyl palmitate, retinyl acetate, retinylpropionate), retinal, and/or retinoic acid (including all-trans retinoicacid and/or 13-cis-retinoic acid), more preferably retinoids other thanretinoic acid. These compounds are well known in the art and arecommercially available from a number of sources, e.g., Sigma ChemicalCompany (St. Louis, Mo.), and Boerhinger Mannheim (Indianapolis, Ind.).Other retinoids which are useful herein are described in U.S. Pat. Nos.4,677,120, issued Jun. 30, 1987 to Parish et al.; U.S. Pat. No.4,885,311, issued Dec. 5, 1989 to Parish et al.; U.S. Pat. No.5,049,584, issued Sep. 17, 1991 to Purcell et al.; U.S. Pat. No.5,124,356, issued Jun. 23, 1992 to Purcell et al.; and U.S. Pat. No.Reissue 34,075, issued Sep. 22, 1992 to Purcell et al. Other suitableretinoids are tocopheryl-retinoate [tocopherol ester of retinoic acid(trans- or cis-), adapalene{6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid}, and tazarotene(ethyl 6-[2-(4,4-dimethylthiochroman-6-yl)-ethynyl]nicotinate).Preferred retinoids are retinol, retinyl palmitate, retinyl acetate,retinyl propionate, retinal and combinations thereof. The retinoid ispreferably substantially pure, more preferably essentially pure. Thecompositions of this invention may contain a safe and effective amountof the retinoid, such that the resultant composition is safe andeffective for regulating keratinous tissue condition, preferably forregulating visible and/or tactile discontinuities in skin, morepreferably for regulating signs of skin aging, even more preferably forregulating visible and/or tactile discontinuities in skin textureassociated with skin aging. The compositions preferably contain from0.005% to 2%, or from 0.01% to 2%, retinoid. Retinol is preferably usedin an amount of 0.01% to 0.15%; retinol esters are preferably used in anamount of from 0.01% to 2% (e.g., 1%); retinoic acids are preferablyused in an amount of 0.01% to 0.25%; tocopheryl-retinoate, adapalene,and tazarotene are preferably used in an amount of from 0.01% to 2%.

A variety of herbal extracts may optionally be included in compositionsof this invention. Illustrative are pomegranate, white birch (Betulaalba), green tea, chamomile, licorice and extract combinations thereof.The extracts may either be water soluble or water-insoluble carried in asolvent which respectively is hydrophilic or hydrophobic. Water andethanol are the preferred extract solvents.

Also included may be such materials as resveratrol, alpha-lipoic acid,ellagic acid, kinetin, retinoxytrimethylsilane (available from ClariantCorp. under the Silcare 1M-75 trademark), dehydroepiandrosterone (DHEA)and combinations thereof. Ceramides (including Ceramide 1, Ceramide 3,Ceramide 3B, Ceramide 6 and Ceramide 7) as well as pseudoceramides mayalso be utilized for many compositions of the present invention but mayalso be excluded. Amounts of these materials may range from 0.000001 to10%, preferably from 0.0001 to 1%.

The personal care composition may further include about 0.1 wt % toabout 8 wt % of a film forming polymer. Such film-forming polymersinclude, but are not limited to, polyalkyleneoxy terminated polyamides(e.g., INCI name: Polyamide-3, Polyamide-4), polyether polyamides (e.g.,INCI name: Polyamide-6), mixed acid terminated polyamides (e.g., INCIname: Polyamide-7), and ester terminated poly(ester-amides) (e.g., INCIname: Polyamide-8). Such film forming polymers may be synthesized or areavailable commercially, such as under the Sylvaclear™ line of productsby Arizona Chemical Company, LLC and the OleoCraft™ line of products byCroda International PLC. Film-forming polymers also include, but are notlimited to, the INCI named Polyester-5 (e.g., Eastman AQ™ 38S Polymer),PPG-17/IPDI/DM PA Copolymer (e.g., Avalure™ UR 450 Polymer), AcrylatesCopolymer (e.g., Avalure™ AC 120 Polymer), and polysaccharides such asXilogel (tamarin gum), lotus bean gums, tara gum, beta glucan, pullulan,carboxymethyl cellulose, hydroxypropyl cellulose, sodium alginate,potato starch, carrageenan. The film forming polymer may includecombinations of any two or more of the polymers recited above. Theamount of film forming polymer in the personal care composition may be0.1 wt % to 8 wt %.

Preservatives can desirably be incorporated into the compositions ofthis invention to protect against the growth of potentially harmfulmicroorganisms. Suitable traditional preservatives for compositions ofthis invention are alkyl esters of para-hydroxybenzoic acid. Otherpreservatives which have more recently come into use include hydantoinderivatives, propionate salts, and a variety of quaternary ammoniumcompounds. Cosmetic chemists are familiar with appropriate preservativesand routinely choose them to satisfy the preservative challenge test andto provide product stability. Particularly preferred preservatives areiodopropynyl butyl carbamate, phenoxyethanol, caprylyl glycol, C₁₋₆parabens (especially, methyl paraben and/or propyl paraben),imidazolidinyl urea, sodium dehydroacetate and benzyl alcohol. Thepreservatives should be selected having regard for the use of thecomposition and possible incompatibilities between the preservatives andother ingredients in the emulsion. Preservatives are preferably employedin amounts ranging from 0.01% to 2%. An especially preferred combinationis octocrylene and caprylyl glycol, since caprylyl glycol has beendisclosed to enhance UVA and UVB protection.

Anti-fungal agents suitable for inclusion in personal care compositionsare well known to one of skill in the art. Examples include, but are notlimited to, climbazole, ketoconazole, fluconazole, clotrimazole,miconazole, econazole, etaconazole, terbinafine, salts of any one ormore of these (e.g., hydrochloride salts), zinc pyrithione, seleniumdisulfide, and combinations of any two or more thereof.

In some embodiments, the personal care compositions of the presentinvention include vitamins. Illustrative vitamins are Vitamin A(retinol), Vitamin B2, Vitamin B3 (niacin), Vitamin B6, Vitamin B12,Vitamin C, Vitamin D, Vitamin E, Vitamin K and Biotin. Derivatives ofthe vitamins may also be employed. For instance, Vitamin C derivativesinclude ascorbyl tetraisopalmitate, magnesium ascorbyl phosphate andascorbyl glycoside. Derivatives of Vitamin E include tocopheryl acetate,tocopheryl palmitate and tocopheryl linoleate. DL-panthenol andderivatives may also be employed. In some embodiments, the Vitamin B6derivative is Pyridoxine Palmitate. In some embodiments, the Vitamin B3derivative is nicotinamide riboside. Flavonoids may also be useful,particularly glucosyl hesperidin, rutin, and soy isoflavones (includinggenistein, daidzein, equol, and their glucosyl derivatives) and mixturesthereof. Total amount of vitamins or flavonoids when present may rangefrom 0.0001% to 10%, alternatively from 0.001% to 10%, alternativelyfrom 0.01% to 10%, alternatively from 0.1% to 10%, alternatively from 1%to 10%, alternatively from 0.01% to 1%, alternatively from 0.1% to 0.5%.

In some embodiments, the personal care compositions of the presentinvention include an enzyme such as, for example oxidases, proteases,lipases and combinations thereof. In some embodiments, the personal carecompositions of the present invention includes superoxide dismutase,commercially available as Biocell SOD from the Brooks Company, USA.

In some embodiments, the personal care compositions of the presentinvention include desquamation promoters. In some embodiments, thepersonal care compositions of the present invention include desquamationpromoters at a concentration from 0.01% to 15%, alternatively from 0.05%to 15% alternatively from 0.1% to 15%, alternatively from 0.5% to 15%

Illustrative desquamation promoters include monocarboxylic acids.Monocarboxylic acids may be substituted or unsubstituted with a carbonchain length of up to 16. In some embodiments, the carboxylic acids arethe alpha-hydroxycarboxylic acids, beta-hydroxycarboxylic orpolyhydroxycarboxylic acids. The term “acid” is meant to include notonly the free acid but also salts and C₁-C₃₀ alkyl or aryl estersthereof and lactones generated from removal of water to form cyclic orlinear lactone structures. Representative acids include glycolic, lacticmalic and tartaric acids. In some embodiments, the salt is ammoniumlactate. In some embodiments, the beta-hydroxycarboxylic acid issalicylic acid. In some embodiments, the phenolic acids include ferulicacid, salicylic acid, kojic acid and their salts.

In some embodiments, the at least one additional component may bepresent from 0.000001% to 10%, alternatively from 0.00001% to 10%,alternatively from 0.0001% to 10%, alternatively from 0.001% to 10%,alternatively from 0.01% to 10%, alternatively from 0.1% to 10%,alternatively from 0.0001% to 1% by weight of the composition.Colorants, opacifiers or abrasives may also be included in compositionsof the present invention. The colorants, opacifiers or abrasives may beincluded at a concentration from 0.05% to 5%, alternatively between 0.1%and 3% by weight of the composition.

In some embodiments, the personal care product of the present inventionmay also include a peptide, such as, for example, the commerciallyavailable pentapeptide derivative—Matrixyl™, which is commerciallyavailable from Sederma, France. In another example, in some embodiments,the personal care product of the present invention may also includeCarnosine.

The compositions of the present invention can comprise a wide range ofother optional components. The CTFA Cosmetic Ingredient Handbook, SecondEdition, 1992, which is incorporated by reference herein in itsentirety, describes a wide variety of non-limiting cosmetic andpharmaceutical ingredients commonly used in the topical cosmetic skincare industry, which are suitable for use in the compositions of thepresent invention. Examples include: antioxidants, binders, biologicaladditives, buffering agents, colorants, thickeners, polymers,astringents, fragrance, humectants, opacifying agents, conditioners,exfoliating agents, pH adjusters, preservatives, natural extracts,essential oils, skin sensates, skin soothing agents, and skin healingagents.

Form of the Composition

The compositions of the present invention are preferably non-solid. Thecompositions of the invention are preferably leave-on compositions. Thecompositions of the present invention are preferably leave-oncompositions to be applied to remain on the skin. These leave-oncompositions are to be distinguished from compositions which are appliedto the skin and subsequently removed either by washing, rinsing, wiping,or the like either after or during the application of the product.Surfactants typically used for rinse-off compositions havephysico-chemical properties giving them the ability to generatefoam/lather in-use with ease of rinse; they can consist of mixtures ofanionic, cationic, amphoteric, and nonionic. Surfactants used inleave-on compositions on the other hand are not required to have suchproperties. Rather, as leave-on compositions are not intended to berinsed-off they need to be non-irritating and therefore it is necessaryto minimize the total level of surfactant and the total level of anionicsurfactant in leave-on compositions. The total level of surfactant inthe inventive compositions is preferably from 1% no more than 15%, morepreferably below 10%, most preferably at most 9%, optimally at most 6%.

In some embodiments, anionic surfactants are present in the leave-onskin care composition in an amount of 0.01% to at most 5% by weight ofthe composition, alternatively from 0.01% to 4% by weight of thecomposition, alternatively from 0.01% to 3% by weight of thecomposition, alternatively from 0.01% to 2% by weight of thecomposition, alternatively substantially absent (less than 1%, or lessthan 0.1%, or less than 0.01%). In some embodiments, the total level ofsurfactant in the skin care compositions is no more than 15%,alternatively below 10%, alternatively at most 9%.

In some embodiments, the surfactant is selected from the groupconsisting of anionic, nonionic, cationic and amphoteric actives.

In some embodiments, nonionic surfactants are those with a C₁₀-C₂₀ fattyalcohol or acid hydrophobe condensed with from 2 to 100 moles ofethylene oxide or propylene oxide per mole of hydrophobe; C₂-C₁₀ alkylphenols condensed with from 2 to 20 moles of alkylene oxide; mono- anddi-fatty acid esters of ethylene glycol; fatty acid monoglyceride;sorbitan, mono- and di-C₈-C₂₀ fatty acids; and polyoxyethylene sorbitanas well as combinations thereof. In some embodiments, the non-ionicsurfactant is selected from the group consisting of alkylpolyglycosides, saccharide fatty amides (e.g. methyl gluconamides) andtrialkylamine oxides.

Amphoteric surfactants suitable in skin care compositions according tosome embodiments of the present invention include cocoamidopropylbetaine, C₁₂-C₂₀ trialkyl betaines, sodium lauroamphoacetate, and sodiumlaurodiamphoacetate.

Anionic surfactants suitable in skin care compositions according to someembodiments of the present invention include soap, alkyl ether sulfatesand sulfonates, alkyl sulfates and sulfonates, alkylbenzene sulfonates,alkyl and dialkyl sulfosuccinates, C₈-C₂₀ acyl isethionates, C₈-C₂₀alkyl ether phosphates, C₈-C₂₀ sarcosinates, C₈-C₂₀ acyl lactylates,sulfoacetates and combinations thereof.

The compositions of the present invention are typically in the form ofemulsions, which may be oil-in-water, or water-in-oil. In someembodiments the personal care compositions are vanishing creams andcreams or lotions based on an oil-in-water emulsion. Vanishing creambase is one which comprises 5 to 40% fatty acid and 0.1 to 20% soap. Insuch creams, the fatty acid is preferably substantially a mixture ofstearic acid and palmitic acid and the soap is preferably the potassiumsalt of the fatty acid mixture, although other counterions and mixturesthereof can be used. The fatty acid in vanishing cream base is oftenprepared using hysteric acid which is substantially (generally about 90to 95%) a mixture of stearic acid and palmitic acid. A typical hystericacid comprises about 52-55% palmitic acid and 45-48% stearic acid of thetotal palmitic-stearic mixture. Thus, inclusion of hysteric acid and itssoap to prepare the vanishing cream base is within the scope of thepresent invention. It is particularly preferred that the compositioncomprises higher than 7%, preferably higher than 10%, more preferablyhigher than 12% fatty acid. A typical vanishing cream base is structuredby a crystalline network and is sensitive to the addition of variousingredients.

In one embodiment, the personal care composition is formulated as awater-in-oil emulsion with cystine substantially solubilized in theaqueous phase. In one embodiment, the personal care composition isformulated as a water-in-oil emulsion with cystine in the aqueousdroplets, with at least 90% of the droplets having a diameter in therange of from 100 nm to 20 microns, or in the alternative from 200 nm to20 microns, or to 10 microns.

In some embodiments, in addition to containing the GSH precursor, thepersonal care composition is formulated as a facial mask. In someembodiments, in addition to containing the GSH precursor, the personalcare composition is formulated as a facial mask according to theformulations described in U.S. Pat. No. 5,139,771. In some embodiments,in addition to containing the GSH precursor, the personal carecomposition is formulated as a facial mask according to the formulationsdescribed in U.S. Pat. No. 4,933,177. In some embodiments, in additionto containing the GSH precursor, the personal care composition isformulated as a facial mask according to the formulations described inU.S. Pat. No. 6,001,367.

In some embodiments, in addition to containing the GSH precursor, thepersonal care composition is formulated as a shampoo. In someembodiments, the personal care compositions of the present invention areformulated as a deodorant. In some embodiments, in addition tocontaining the GSH precursor, the personal care composition isformulated as a deodorant according to the formulations described inU.S. Pat. No. 7,282,471. In some embodiments, the personal carecompositions of the present invention are formulated as anantiperspirant. In some embodiments, in addition to containing the GSHprecursor, the personal care composition is formulated as anantiperspirant according to the formulations described in U.S. Pat. No.7,282,471.

In some embodiments, the personal care compositions of the presentinvention are formulated as a single use personal care toweletteproduct. In some embodiments, in addition to containing the GSHprecursor, the personal care composition is formulated as a single usepersonal care towelette product according to the formulations describedin U.S. Pat. No. 7,282,471.

In some embodiments, the personal care compositions of the presentinvention are formulated as a soap bar. In some embodiments, in additionto containing the GSH precursor, the personal care composition isformulated as a soap bar according to the formulations described in U.S.Pat. No. 7,282,471.

Methods of Making Skin Care Compositions

In some embodiments, skin care compositions according to the presentinvention can be made by:

-   a. mixing all water soluble ingredients including preservatives,    thickening polymer, optionally glycerine, and water;-   b. heating the mixture to a temperature of 70-90° C.;-   c. mixing all the oil soluble ingredients and the compound of    formula (1) to a temperature of 70-90° C.;-   d. adding the mixed oil soluble ingredients to the heated mixture of    water soluble ingredients, and mixing via agitation, maintaining the    mixture at a temperature of 70-90° C.; and-   e. cooling the mixture to room temperature, whilst mixing.    In some embodiments the personal care compositions of the invention    are prepared by making an emulsion:-   a. solubilizing cystine at the desired level in high pH (9 to 14, or    9 to 12) aqueous solution-   b. preparing a macroemulsion in oil with this solution with an    emulsifier, then-   c. adding, with mixing, an acidic aqueous solution to obtain an    emulsion with pH within a neutral range required for the topical    composition and, lastly,-   d. subjecting the emulsion to high shear, or homogenization, or    sonolation step e.g. via a homogenizer_such as Nano DeBee    homogenizer of BEE International (Massachusetts, USA) or a Sonolator    homogenizer manufactured by Sonic Corporation (Connecticut, USA), to    produce a homogeneous neutral pH range final emulsion with more than    90% of the droplets having a diameter in the size range of from 100    nm to 20 microns.

Method of Using the Skin Care Compositions

In some embodiments, the skin care composition is topically applied tohuman skin. In some embodiments, the skin care composition provides atleast one benefit, selected from the group consisting of: skinconditioning, skin smoothening, reduction of wrinkled or aged skin,reduction of inflammation of the skin, reduction of dryness, reductionof age spots, reduction of sun burn, and lightening of the skin.

In some embodiments, a small quantity of the skin care composition, forexample from 1 to 5 ml, is applied to exposed area of the skin, from asuitable container or applicator and, if necessary, it is then spreadover and/or rubbed into the skin using the hand or fingers or a suitabledevice.

Reference is now made to the following examples, which together with theabove descriptions illustrate some embodiments of the invention innon-limiting examples.

EXAMPLES Experimental Methods

Powders of the following amino acids (pyroglutamic acid and glycine)were purchased from Sigma, and individual stock solutions of each aminoacid prepared by reconstitution of the powder in water (pH 7). All aminoacids were L stereo isomers. Cystine (Sigma) stock solutions weregenerated in 0.5M sodium hydroxide (pH 12) as cystine is poorly solublein neutral solutions. Cystine esters, ditert-butyl L-cystinatedihydrochloride (DTBC) and diethyl L-cystinate dihydrochloride (DEC)were purchased from Bachem; L-Cystine dimethyl ester dihydrochloride(CDME) was from Sigma. Sodium pyroglutamic acid (also known as sodiumpyrrolidone carboxylate (NaPCA)) was supplied as a 50% solution in waterfrom Ajinomoto. To generate the mixture henceforth described as GAP,appropriate volumes of three amino acids (glutamate source (i.e NaPCA),cystine, and glycine) were combined in Hank's Balanced Salt Solution(Sigma) such that the glutamate source, cystine, and glycine were in a0.5:1:1 weight ratio. The specific concentrations used in each assay arereferenced below.

Additional test reagents: 4-ethylresorcinol (Alfa Aesar, Sigma-Aldrich,and TCI), 4-hexylresorcinol (Sigma-Aldrich), 4-butylresorcinol (ViviMedLabs and TCI), 4-isopropylresorcinol (AV Square Chem),4-(1-phenylethyl)resorcinol (Symrise Inc. and TCI), 4-methylresorcinol(Sigma-Aldrich), olivetol (Sigma-Aldrich), 3-hydroxytyrosol(Sigma-Aldrich and TCI), and 4-(cyclohexylmethyl)resorcinol (prepared asdescribed in U.S. Pat. No. 7,468,464). These reagents were typicallysolubilized in ethanol or dimethyl sulfoxide. In assays below,appropriate volumes were added to vehicle control samples to normalizefor potential solvent effects.

Glutathione Assay

Aged Human Keratinocytes (Cascade Biologics, now ThermoFisherScientific, Waltham, Mass.) were maintained in EpiLife® mediumcontaining 60 uM calcium chloride and 1% Human Keratinocyte GrowthSupplement (both media components from ThermoFisher Scientific) in ahumidified incubator with an atmosphere containing 5% CO₂ at 37° C. Themedium was refreshed every 2-3 days. Subsequently, cells weretrypsinized at 90% confluency and seeded at a density of 1×10⁴ per wellinto 96-well plates with white wall and clear bottom. One or two daysafter seeding, cell medium was replaced with Hank's Balanced SaltSolution (HBSS), and keratinocytes were pre-treated with GAP (or0.12-0.240 mM sodium hydroxide vehicle control, pH 7.5) alone or incombination with additional test reagents described above or L-cystineesters alone for 1-2 hours. The concentration of all amino acidsconstituting the GAP mixture used in this assay are designated in thedata tables, and fully described in the abbreviations list below.

After one or two hours of pre-treatment with GAP or additional testreagents, alone or in combination, keratinocytes were then challengedwith 25 uM menadione (Sigma-Aldrich), a known inducer of oxidativestress. After 18-20 hours, cells were harvested and analyzed for totalglutathione levels using a commercially available kit (GSH-GSSG GLoAssay, Promega), a luminescence-based system for the detection andquantification of total glutathione in cultured cells. In summary, aftercell treatment, the media was removed and replaced with a cell lysisreagent for 5 minutes at 20-25° C.; note, all remaining steps were alsoconducted at 20-25° C. Next, a luciferase generation reagent was addedto each well and incubated for 30 minutes. Following this step, aluciferin detection reagent was added to each well and plates wereincubated for 15 minutes. Finally, plates were then read forluminescence in a FlexStation 3 plate reader (Molecular Devices). Totalglutathione levels were calculated after interpolation of glutathioneconcentrations from a standard curve. Experimental conditions weretypically conducted in at least triplicate determinations. Statisticalsignificance was calculated using 1-way ANOVA. Percent protection wascalculated by using the calculated glutathione levels from eachexperiment in the following equation:

${\frac{\left( \text{Test sample} \right) - \left( {\text{vehicle control} + \text{menadione}} \right)}{\text{vehicle control}} \times 100\%}\; = {\%\mspace{14mu}{protection}}$

Reactive Oxygen Species (RSO) Assay

Human Keratinocytes (Promocell, Heidelberg, Germany) were maintained inEpiLife® keratinocyte medium containing 60 uM calcium chloride and 1%Human Keratinocyte Growth Supplement (HKGS) in a humidified incubatorwith an atmosphere containing 5% CO2 at 37° C. The medium was refreshedevery other day. Subsequently, cells were trypsinized at 90% confluencyand seeded at a density of 1-2×10⁴ per well into 96-well plates withblack wall and clear bottom. On the second day after seeding, cellmedium was replaced with Hank's Balanced Salt Solution (HBSS) with orwithout menadione (10-25 uM), GAP (typically at 49 uM pyroglutamic acid,60 uM cystine, 194 uM glycine), GAP vehicle (0.2 mM NaOH, pH 7.5),above-described additional test reagents, or combinations of GAP withadditional test reagents or L-cystine esters alone, and incubated foradditional 18 hours. For ROS detection, CellROX green (Life Tech, ThermoFisher Scientific, Rockford, USA) reagent was added into each well to afinal concentration of 15-25 uM and incubated for additional 2-4 hoursat 37° C. in a humidified incubator. The ROS fluorescence was detectedusing a Tecan microplate reader (Excitation/Emission=490/525). RelativeROS production was calculated with normalization based on the vehiclecontrol treatment which was set to 100%. Where indicated, percentprotection was calculated as a comparison to menadione alone treatment,using the measured relative fluorescent units in the following equation:

${\frac{\left( {\text{vehicle control} + \text{menadione}} \right) - \left( \text{Test sample} \right)}{\left( {\text{vehicle control} + \text{menadione}} \right)} \times 100\%}\; = {\%\mspace{14mu}{protection}}$

ROS levels were evaluated together with cell viability because it ispossible to get a false negative for ROS if treatment is so toxic, thatat the time of assay, cells are dead (and there are no longer anydetectable ROS). Decrease in ROS levels is meaningful if cells are stillviable.

Cell Viability Assay

Human Keratinocytes (Promocell, Heidelberg, Germany) were maintained inEpiLife® keratinocyte medium containing 60 uM calcium chloride and 1%Human Keratinocyte Growth Supplement (HKGS). The medium was refreshedevery other day. Subsequently. cells were trypsinized at 90% confluencyand seeded at a density of 2×10⁴ per well into 96-well transparenttissue culture plates. On the second day after seeding, cell medium wasreplaced with treatments as described above in ROS assay section. After18 hours, Cell Culture Kit-8 (CCK-8) reagent (Dojindo, Kumamoto, Japan)was diluted 1:10 in HBSS and incubated with cells for 4 h at 37° C. in ahumidified incubator. Optical absorption at 450 nm was measured using aTecan Safire2 plate reader. Relative viability was calculated withnormalization based on the vehicle control treatment, which was set to100%.

Where indicated, percent protection was calculated as a comparison tomenadione alone treatment, using the measured relative absorbance unitsin the following equation:

${\frac{\text{Test sample} - \left( {\text{vehicle control} + \text{menadione}} \right)}{\left( {\text{vehicle control} + \text{menadione}} \right)} \times 100\%}\; = {\%\mspace{14mu}{protection}}$

Tyrosinase Activity Assay

Human primary melanocytes (Cascade Biologics, now ThermoFisherScientific) were grown in melanocytes growth medium (MGM) with humanmelanocyte growth supplement (both media components from ThermoFisherScientific). Melanocytes were seeded at 1×10⁴ cells/well in a 96 wellsplate and cultures left undisturbed for 24 hrs in a 5% CO₂ humidifiedincubator at 37° C. At 24hrs post-seeding, cells were treated with GAPamino acids (consisting of glutamine (32 LIM), cystine (40 uM), glycine(129 uM)) alone or in combination with test reagents described above,and left undisturbed for another 72 hours, Subsequently, cell viabilitywas assessed and the cells were then lysed and progressed fordetermination of in situ tyrosinase activity. Cultures were rinsed twicewith 1× phosphate-buffered saline and lysed with 40 uL of 0.5% TritonX100 for 1 hour on an ice bed. In situ tyrosinase activity was visualizedby addition of 60 μl of 50 mM potassium phosphate buffer (pH 6.8)containing 2 mM DOPA (3,4dihydroxy phenylalanine) and 4 mM MBTH reagent(3-Methyl-2-Benzothiazolinone hydrazone hydrochloride) for 1 hour at 37°C. The reaction was stopped by the addition of 100 uL of ice-cold 10%tricholoracetic acid and then centrifuged at approximately 300 g for 10minutes at 4° C. The soluble supernatant was separated from the pelletand the optical density read in a TECAN plate-reader (540 nm filter).The spectrophotometric optical density at 540 nm for untreated cells (noactive) is considered as 100% tyrosinase activity. Tyrosinase activityis expressed after correction for cell numbers (activity/viability) andrepresented as % control.

Abbreviations in the Examples are as follows:

mM=millimolar

uM=micromolar

uL=micro liter

GAP=glutamate and cystine and glycine mix

GAP 5=4 uM sodium pyroglutamic acid, 5 uM cystine, 16 uM glycine

GAP 10=8 uM sodium pyroglutamic acid, 10 uM cystine, 32 uM glycine

GAP 20=16 uM sodium pyroglutamic acid, 20 uM cystine, 64 uM glycine

NaPCA =sodium pyroglutamic acid (also known as sodiumpyrrolidonecarboxylic acid)

HR=4-hexylresorcinol

BR=4-butylresorcinol

IPR=4-isopropylresorcinol

ER=4-ethylresorcinol

PER=4-(1-phenylethyl)resorcinol

MR=4-methylresorcinol

4-CHMR=4-(cyclohexylmethyl)resorcinol

DEC=Diethyl L-cystinate dihydrochloride

CDME=L-Cystine dimethyl ester dihydrochloride

DTBC=Ditert-butyl L-cystinate dihydrochloride

EXAMPLE 1

Example 1 evaluated various combinations of 4-alkyl resorcinols andamino acids constituting GSH building blocks for potentiatingintracellular GSH production. Results that were obtained are summarizedin Tables 1A and 1B.

In Tables 10 through 1H the efficacy of various cystine esters was alsotested.

TABLE 1A Glutathione Synthesis % Protection (improvement Mean vs.vehicle (uM control + Sample glutathione) menadione) A Vehicle Control1.75 B Vehicle Control + menadione 0.07¹   0¹ Test Samples C GAP 10 +menadione 1.34^(1, 2, 3)  72^(1, 2, 3) D GAP 20 + menadione 4.61^(2, 3)259^(2, 3) E HR (20 uM) + menadione 0.46¹  22¹ F HR (20 uM) + cystine +menadione 2.81^(1, 2, 3) 156^(1, 2, 3) 1 HR (20 uM) + GAP 10 4.00^(2, 3)224^(2, 3) (NaPCA + glycine + cystine) + menadione 2 HR (20 uM) +NaPCA + cystine + 4.20^(2, 3) 236^(2, 3) menadione 3 HR (20 uM) +glycine + cystine + 3.64^(2, 3) 204^(2, 3) menadione Staisticallysignificant decrease: ¹p < 0.05 compared to HR + GAP10 + menadioneStatistically significant improvement: ²p < 0.05 compared to vehiclecontrol + menadione ³p < 0.05 compared to HR + menadioneSamples A through G were outside the scope of the invention. Sample Dwas a positive control as it employed a high concentration of GAP. Itcan be seen from the results in Table 1A that a combination of HR withcystine and glutamate (Samples 1 and 2 within the scope of theinvention) or with cystine and glycine (Sample 3) resulted insynergistic increase in GSH synthesis compared to the GSH synthesisachieved with either resorcinol or GAP alone (Samples E and C,respectively), or combination of HR with cystine alone (Sample G).Samples 1 to 3 performed on par with positive control (Sample D), yet atlower concentration of GAP and therefore at lower concentration ofcystine, therefore counterbalancing the problem of having to solubilizerelatively high amounts of cystine.

TABLE 1B Glutathione Synthesis % Portection (improvement Mean vs.vehicle (uM control + Sample gluthatione) menadione) A Vehicle Control1.75 B Vehicle Control + menadione 0.07¹   0 Test Samples C GAP 10 +menadione 1.34^(1, 2, 3)  72^(1, 2, 3) D GAP 20 + menatione 4.61^(2, 3)259^(2, 3) E BR (50 uM) + menadione 0.06¹  −1¹ F BR (50 uM) + glycine +cystine + 1.25^(1, 2, 3)  67^(2, 3) menadione G BR (50 uM) + cystine +1.73^(2, 3)  95^(2, 3) menadione 1 BR (50 uM) + GAP 10 2.22^(2, 3)122^(2, 3) (NaPCA + glycine + cystine) + menadione 2 BR (50 uM) +NaPCA + cystine + 2.27^(2,3) 125^(2,3) menadione Staisticallysignificant decrease: ¹p < 0.05 compared to BR + GAP10 + menadioneStatistically significant improvement: ²p < 0.05 compared to vehiclecontrol + menadione ³p < 0.05 compared to BR + menadioneSamples marked by alphabetical characters (A through H above) wereoutside the scope of the invention. Numerically marked samples werewithin the scope of the invention. Sample D was a positive control as itemployed a high concentration of GAP. It can be seen from the results inTable 1B that when 4-alkyl resorcinol is BR, unlike in Table 1A with HR,both cystine and glutamate appear to be needed (but not glycine) toachieve synergistic increase in GSH synthesis: Samples 1 and 2, withinthe scope of the invention, resulted in synergistic increase in GSHsynthesis compared to the GSH synthesis achieved with either BR or GAPalone (Samples E and C, respectively), or combination of the BR withcystine alone (Sample G) or combination of BR with cystine and glycine,without glutamate (Sample F). Samples 1 and 2 within the scope of theinvention achieved about double GSH synthesis improvement compared withSamples E, C, F, and G.

TABLE 1C Glutathione Synthesis % Protection (improvement vs. Mean (μmvehicle control + Sample glutathione) menadione) A Vehicle control 2.73B Vehicle control + Menadione 0.18¹  0 C DEC (40 uM) + Menadione0.54^(1,2) 13^(1,2) D DEC (80 uM) + Menadione 2.72² 93² Statisticallysignificant decrease: ¹p < 0.05 compared to vehicle controlStatistically significant improvement: ²p < 0.05 compared to vehiclecontrol + menadione

TABLE 1D Reduction in Reactive Oxygen Species % Protection Cell %protection (improvement viability (improvement ROS inhibition vs.vehicle (% of vs. vehicle (% of vehicle control + vehicle control +Sample control) menadione) control) menadione) Vehicle control 100 100Vehicle control + Menadione 375.5¹  73.7¹ DEC (20 uM) + Menadione232.8^(1, 2) 38.0^(1, 2) 109.8² 48.9² DEC (40 uM) + Menadione211.9^(1, 2) 43.6^(1, 2) 127.3^(1, 2) 72.7^(1, 2) DEC (80 uM) +Menadione 233.8^(1, 2) 37.7^(1, 2) 131.5^(1, 2) 78.3^(1, 2) DEC (160uM) + Menadione 253.8^(1, 2) 32.4^(1, 2) 122.3^(1, 2) 65.9^(1, 2)Statistically significant difference: ¹p < 0.05 compared to vehiclecontrol Statistically significant difference: ²p < 0.05 compared tovehicle control + menadione

TABLE 1E Glutathione Synthesis % Protection (improvement vs. Mean (μmvehicle control + Sample glutathione) menadione) A Vehicle control 2.73B Vehicle control + Menadione 0.18¹ 0 C DTBC (40 uM) + Menadione 0.17¹0¹ D DTBC (80 uM) + Menadione 0.19¹ 1¹ Statistically significantdecrease: ¹p < 0.05 compared to vehicle control

TABLE 1F Reduction in Oxygen Species ROS % Protection Cell % protectioninhibition (improvement viability (improvement (% of vs. vehicle (% ofvs. vehicle vehicle control + vehicle control + Sample control)menadione) control) menadione) Vehicle control 100 100 Vehicle control +Menadione 375.5¹  73.7¹ DTBC (20 uM) + Menadione 367.0¹  2.2  78.1¹ 6.0¹ DTBC (40 uM) + Menadione 323.7^(1, 2) 13.8^(1, 2)  75.91  3.0¹DTBC (80 uM) + Menadione 268.7^(1, 2) 28.4^(1, 2)  73.61 −0.1¹ DTBC (160uM) + Menadione 221.1^(1, 2) 41.1^(1, 2) 104.2² 41.3² Statisticallysignificant difference: ¹p < 0.05 compared to vehicle controlStatistically significant difference: ²p < 0.05 compared to vehiclecontrol + menadione

TABLE 1G Glutathione Synthesis % Protection (improvement vs. Mean (μmvehicle control + Sample glutathione) menadione) A Vehicle control 2.96B Vehicle control + Menadione 0.18¹  0 C CDME (80 uM) + Menadione1.09^(1, 2) 31^(1, 2) Statistically significant decrease: ¹p < 0.05compared to vehicle control Statistically significant improvement: ²p <0.05 compared to vehicle control + menadione

TABLE 1H Reduction in Oxygen Species ROS % Protection Cell % protectioninhibition (improvement viability (improvement (% of vs. vehicle (% ofvs. vehicle vehicle control + vehicle control + Sample control)menadione) control) menadione) Vehicle control 100 100 Vehicle control +Menadione 131.8¹  69.8¹ CDME (20 uM) + Menadione 107.8² 18.2² 90.9^(1, 2) 30.2^(1, 2) CDME (40 uM) + Menadione 111.3^(1, 2)15.5^(1, 2)  93.1^(1, 2) 33.4^(1, 2) CDME (80 uM) + Menadione114.3^(1, 2) 13.3^(1, 2)  87.0^(1, 2) 24.6^(1, 2) CDME (160 uM) +Menadione  97.9² 25.7² 105.9^(1, 2) 51.7^(1, 2) Statisticallysignificant difference: ¹p < 0.05 compared to vehicle controlStatistically significant difference: ²p < 0.05 compared to vehiclecontrol + menadione

EXAMPLE 2

Example 2 evaluated various combinations of 4-alkyl resorcinols andamino acids constituting GSH building blocks for potentiatingintracellular GSH production and improved reduction in oxygen species.Results that were obtained are summarized in Tables 2A through 2F.

TABLE 2A Glutathione Synthesis % Protection (improvement Mean vs.vehicle (uM control + Sample glutathione) menadione) A Vehicle Control2.08 B Vehicle Control + Menadione 0.17  0 Test Samples C HR (10 uM) +Menadione 0.24  4 D HR (20 uM )+ Menadione 0.28  5 E HR (40 uM) +Menadione 0.19  1 F HR (60 uM) + Menadione 0.14  0 G GAP 5 + Menadione0.57¹  19¹ H GAP 10 + Menadione 1.51¹  65¹ I GAP 20 + Menadione3.89^(1, 2) 187^(1, 2) 1 HR (10 uM) + GAP 5 + Menadione 0.50  16 2 HR(20 uM) + GAP 5 + Menadione 0.76¹  28 3 HR (40 uM) + GAP 5 + Menadione0.47  15 4 HR (60 uM) + GAP 5 + Menadione 0.16  0 5 HR (10 uM) + GAP10 + Menadione 2.85^(1, 2, 3) 129^(1, 2, 3) 6 HR (20 uM) + GAP 10 +Menadione 2.97^(1, 2, 3) 135^(1, 2, 3) 7 HR (40 uM) + GAP 10 + Menadione0.82³  31³ 8 HR (60 uM) + GAP 10 + Menadione 0.15  0 Statisticallysignificant improvement: ¹p < 0.05 compared to vehicle control +menadione ²p < 0.05 compared to GAP10 + menadione ³p < 0.05 compared toHR (at equivalent dose) + menadione

TABLE 2B Glutathione Synthesis % Protection (improvement vs. Meanvehicle control + Sample (uM glutathione) menadione) A Vehicle Control1.87 B Vehicle Control + Menadione 0.01  0 Test Samples C BR (10 uM) +Menadione 0.10  5 D BR (50 uM) + Menadione 0.07  3 E BR (100 uM) +Menadione 0.13  6 F IPR (10 uM) + Menadione 0.12  6 G IPR (50 uM) +Menadione 0.12  6 H IPR (100 uM) + Menadione 0.16  8 I GAP 10 +Menadione 0.70¹  37¹ J GAP 20 + Menadione 2.71^(1,2) 144^(1,2) 1 BR (10uM) + GAP 10 + 0.88^(1,3)  46^(1,3) Menadione 2 BR (50 uM) + GAP 10 +1.51^(1,2,3)  80^(1,2,3) Menadione 3 BR (100 uM) + GAP 10 + 0.93^(1,3) 49^(1,3) Menadione 4 IPR (10 uM) + GAP 10 + 1.02^(1,4)  54^(1,4)Menadione 5 IPR (50 uM) + GAP 10 + 1.14^(1,2,4)  60^(1,2,4) Menadione 6IPR (100 uM) + GAP 10 + 1.13^(1,2,4)  60^(1,2,4) Menadione Statisticallysignificant improvement: ¹p < 0.05 compared to vehicle control +menadione ²p < 0.05 compared to GAP10 + menadione ³p < 0.05 compared toBR (at equivalent dose) + menadione ⁴p < 0.05 compared to IPR (atequivalent dose) + menadione

TABLE 2C Glutathione Synthesis % Protection (improvement vs. Meanvehicle control + Sample (uM glutathione) menadione) A Vehicle Control2.65 B Vehicle Control + Menadione 0.36    0 Test Samples C GAP 10 +Menadione 2.47¹    80¹ D ER (40 uM) + Menadione 0.36    0 E ER (50 uM) +Menadione 0.25  −4 F ER (60 uM) + Menadione 0.34  −1 1 ER (40 uM) + GAP10 + 2.17^(1,3)    68^(1,3) Menadione 2 ER (50 uM) + GAP 10 +2.82^(1,2,3)    93^(1,2,3) Menadione 3 ER (60 uM) + GAP 10 +3.62^(1,2,3)   123^(1,2,3) Menadione Statistically significantimprovement: ¹p < 0.05 compared to vehicle control + menadione ²p < 0.05compared to GAP10 + menadione ³p < 0.05 compared to ER (at equivalentdose) + menadioneIn Tables 2A-2C, samples marked by alphabetical characters were outsidethe scope of the invention. Sample I (Table 2A) and Sample J (Table 2B)were positive controls as they employed a high concentration of GAP.Overall, it can be seen from the results in Tables 2A-2C thatcombination of 4-alkyl resorcinol (HR, BR, IPR, or ER) concentrationswith GAP amino acids resulted in synergistic increase in GSH synthesiscompared to the GSH synthesis achieved with either resorcinol or GAPalone.

TABLE 2D Reduction in Oxygen Species Mean ROS production % protectionCell % Protection (% of (improvement vs viability (improvement vsvehicle vehicle control + (% of vehicle control + Sample control)menadione) control) menadione) A Vehicle Control 100.0 100.0 B VehicleControl + 504.8  54.8 Menadione Test Samples C Menadione + GAP 171.5³66.02³  92.7³   69.11³ D Menadione + HR 153.4³ 69.6³  65.1³   18.85³ (10uM) E Menadione + HR 118.7³ 76.49³  11.0 −79.00 (20 uM) 1 Menadione + HR108.9^(1,2,3) 78.42^(1,2,3) 103.2^(2,3)   88.30^(2,3) (10 uM) + GAP 2Menadione + HR  92.5^(1,2,3) 81.68^(1,2,3) 105.2^(1,2,3)   92.02^(1,2,3)(20 uM) + GAP Statistically significant improvement: ¹p < 0.05 comparedto menadione + GAP ²p < 0.05 compared to menadione + HR (at equivalentdose) ³p < 0.05 compared to vehicle control + menadione

TABLE 2E Reduction in Oxygen Species Mean ROS production % Protectioncell % Protection (% of (improvement vs viability (improvement vsvehicle vehicle control + (% of vehicle control + Sample control)menadione) control) menadione) A Vehicle control 100.0 100.0 BMenadione + 222.8  66.3 Vehicle Control Test Samples C Menadione + GAP136.5³ 38.70³  84.5³ 27.41³ D Menadione + BR 220.7  0.95  74.1³ 11.75³(20 uM) 1 Menadione + GAP + 122.2^(1,2,3) 45.20^(1,2,3)  90.9^(1,2,3)37.07^(1,2,3) BR (20 uM) Statistically significant improvement: ¹p <0.05 compared to menadione + GAP ²p < 0.05 compared to menadione + BR ³p< 0.05 compared to vehicle control + menadione

TABLE 2F Reduction in Oxygen Species Mean ROS production % protectionCell % protection (% of (improvement vs viability (improvement vsvehicle vehicle control + (% of vehicle control + Sample control)menadione) control) menadione) A Vehicle Control 100.0 100 B Menadione +301.2  61.7 Vehicle Control Test Samples C Menadione + GAP 192.0³  36.26³  76.0³ 23.23³ D Menadione + PER 321.5  −6.74  62.3  1.09 (20uM) 1 Menadione + GAP + 175.5^(1,2,3)   41.72^(1,2,3)  90.7^(1,2,3)47.13^(1,2,3) PER (20 uM) Statistically significant improvement: ¹p <0.05 compared to menadione + GAP ²p < 0.05 compared to menadione + PER³p < 0.05 compared to vehicle control + menadioneIn Tables 2D-F, samples marked by alphabetical characters were outsidethe scope of the invention. Overall, it can be seen from the results inTables 2D-F that combination of 4-alkyl resorcinol (HR, BR or PER) withGAP amino acids resulted in a synergistic decrease in ROS productioncompared to ROS levels achieved with either resorcinol alone or GAPalone.

TABLE 2G Glutathione Synthesis % Protection (improvement vs Mean vehiclecontrol + Sample (uM glutathione) menadione) A Vehicle Control 2.76 BVehicle Control + Menadione 0.16    0 Test Samples C GAP 10 + Menadione2.88¹   98¹ D PER (10 uM) + Menadione 0.12  −2 E PER (20 uM) + Menadione0.25    3 F PER (50 uM) + Menadione 0.50   12 1 PER (10 uM) + GAP 10 +2.70   92 Menadione 2 PER (20 uM) + GAP 10 + 1.62   53 Menadione 3 PER(50 uM) + GAP 10 + 1.05   32 Menadione Statistically significantimprovement: ¹p < 0.05 compared to vehicle control + menadione

TABLE 2H Reduction in Oxygen Species Mean ROS production Cell viability(% of vehicle (% of vehicle Sample control) of control) A VehicleControl 100 100.0 B Menadione + Vehicle Control 311.0  35.5 Test SamplesC Menadione + GAP 156.5¹ 132.61 D Menadione + ER (10 uM) 287.5  36.6 EMenadione + ER (20 uM) 308.3  39.8 1 Menadione + ER (10 uM) + GAP 166.1¹126.4¹ 2 Menadione + ER (20 uM) + GAP 162.7¹ 122.3¹ Statisicallysignificant improvement: ¹p < 0.05 compared to vehicle control +menadione

It can be seen from the results in Table 2G that when PER was tested inGlutathione Assay with GAP amino acids synergistic increase in GSHsynthesis was not observed, although the same PER/GAP combination didprovide synergistic decrease in in reactive oxygen species—see Table 2F.

On the other hand, results in Table 2H show that when ER was tested inreduction in oxygen species assay, with GAP amino acids synergisticdecrease in reactive oxygen species was not observed, although the sameER/GAP combination did provide synergistic increase in GSH synthesis—seeTable 2C. Thus, the results in Tables 2G and 2H suggest that the twoassays used to evaluate the anti-oxidant activity are not always inagreement, indicating that it may be adviseable to perform both assays,before concluding with certainty the absence of the antioxidantpotential.

COMPARATIVE EXAMPLE b 3

Comparative Example 3 investigated glutathione synthesis and reductionin oxygen species of combinations of amino acids and 5-substitutedresorcinols (Olivetol, also known as 5-pentylresorcinol), non-resorcinolmolecules (3-hydroxytyrosol) or 4-methyl-resorcinol (shorter branch thanethyl), and 4-(cyclohexylmethyl)-resorcinol. The results that wereobtained are summarized in Tables 3A through 3D.

TABLE 3A Glutathione Synthesis % Protection (improvement vs Mean vehiclecontrol + Sample (uM glutathione) menadione) Vehicle Control 2.76Vehicle Control + Menadione 0.16    0 Test Samples GAP 10 + Menadione2.88¹    98¹ Olivetol (10 uM) + Menadione 0.14  −1 Olivetol (20 uM) +Menadione 0.13  −1 Olivetol (50 uM) + Menadione 0.11  −2 Olivetol (10uM) + GAP 10 + 1.55    50 Menadione Olivetol (20 uM) + GAP 10 + 1.43   46 Menadione Olivetol (50 uM) + GAP 10 + 1.35    43 Menadione3-hydroxytyrosol (10 uM) + 0.07  −3 Menadione 3-hydroxytyrosol (20 uM) +0.03  −5 Menadione 3-hydroxytyrosol (50 uM) + 0.04  −4 Menadione3-hydroxytyrosol (10 uM) + GAP 0.33    6 10 + Menadione 3-hydroxytyrosol(20 uM) + GAP 0.31    5 10 + Menadione 3-hydroxytyrosol (50 uM) + GAP0.06  −3 10 + Menadione GAP 20 + Menadione 6.35^(1,2)   224^(1,2)Statistically significant improvement: ¹p < 0.05 compared to vehiclecontrol + menadione ²p < 0.05 compared to GAP10 + menadione

TABLE 3B Reduction in Reactive oxygen species ROS production cellviability (% of vehicle (% vehicle Sample control) of control) VehicleControl 100.0 100.0 Menadione + Vehicle Control 331.1  31.8 Test SamplesMenadione + GAP 145.0¹ 122.9¹ Menadione + 3-hydroxytyrosol 241.6  16.8(10 uM) Menadione + 3-hydroxytyrosol 150.1¹ 105.0¹ (10 uM) + GAPMenadione + 3-hydroxytyrosol 229.9¹  16.5 (20 uM) Menadione +3-hydroxytyrosol 152.4¹ 103.9¹ (20 uM) + GAP Statistically significantimprovement: ¹p < 0.05 compared to vehicle control + menadione

TABLE 3C Reduction in Reactive oxygen species Mean ROS production Cellviability (% of vehicle (% of vehicle Sample control) control) VehicleControl 100.0 100.0 Menadione + Vehicle Control 272.8  51.2 Test SamplesMenadione + GAP 157.2¹ 100.4¹ Menadione + MR (10 uM) 233.5¹  45.3Menadione + MR (10 uM) + GAP 170.0¹  94.5¹ Statistically significantimprovement: ¹p < 0.05 compared to vehicle control + menadione

TABLE 3D Glutathione Synthesis Mean Sample uM glutathione) % ProtectionA Vehicle Control 2.693 B Vehicle Control + Menadione 0.193    0 TestSample C GAP 10 + Menadione 2.302¹    78.3¹ D 4-CHMR (10 uM) + Menadione0.07  −4.6 E 4-CHMR (20 uM) + Menadione 0.026  −6.2 F 4-CHMR (50 uM) +Menadione 0.147  −1.7 G 4-CHMR (10 uM) + GAP 10 + 3.931^(1,3)  138.8^(1,3) Menadione H 4-CHMR (20 uM) + GAP 10 + 4.313^(1,3)  153.0^(1,3) Menadione I 4-CHMR (50 uM) + GAP 10 + 0.147  −1.7Menadione J GAP 20 + Menadione 4.348^(1,2)   154.3^(1,2) Statisticallysignificant improvement: ¹p < 0.05 compared to vehicle control +menadione ²p < 0.05 compared to GAP10 + menadione ³p < 0.05 compared to4-(cyclohexylmethyl)resorcinol (at equivalent dose) + menadione

Collectively, the data in Tables 3A-3D demonstrate that combinations ofGAP with resorcinols outside the scope of the invention—i.e.5-substituted resorcinols (Olivetol, also known as 5-pentylresorcinol),or 4-(cyclohexylmethyl)resorcinol or 4-methylresorcinol—did not resultin either synergistic increase in GSH synthesis or in synergisticdecrease in reactive oxygen species. Likewise, no synergistic effect wasobserved with the non-resorcinol molecule 3-OH tyrosol.

EXAMPLE 4

Example 4 investigated the skin lightening potential of the inventivecompositions. The results that were obtained are summarized in Table 4.

TABLE 4 Tyrosinase activity inhibition Sample Mean of % Inhibition AMedia Control  0 B Vehicle Control  0 Test Samples C GAP  8¹ D HR (10uM) 71¹ E HR (5 uM) 63¹ F ER (10 uM) 68¹ G ER (5 uM) 67¹ 1 GAP + HR (10uM) 70^(1,2) 2 GAP + HR (5 uM) 70^(1,2,3) 3 GAP + ER (10 uM) 76^(1,2,4)4 GAP + ER (5 uM) 75^(1,2,4) Statistically significant improvement: ¹p <0.05 compared to media and vehicle control ²p < 0.05 compared to GAP ³p< 0.05 compared to HR alone (at equivalent doses) ⁴p < 0.05 compared toER alone (at equivalent doses)

In Table 4 samples marked by alphabetical characters were outside thescope of the invention. Numerically marked samples were within the scopeof the invention. It can be seen that, overall, combinations of GAP withresorcinol compounds within the scope of the invention resulted insynergistic decrease in tyrosinase activity compared to the tyrosinaseactivity achieved with either resorcinol or GAP alone.

EXAMPLE b 5

Personal care formulations according to the present invention areillustrated in the Tables below. All numbers in the Tables representweight % in the composition.

TABLE I Oil-in-water formulations, lotions and creams OW-1 OW-2 OW-3OW-4 OW-5 Water To 100 To 100 To 100 To 100 To 100 Glycerine    0-40   1-40    1-5    1-10    1-40 Propylene    0-5    0-5 glycol Butylene   0-5    0-5    0-5 glycol Carbomer    0-2  0.03-1 Ammonium    0-1 0.03-1  0.01-1 Acryloyl dimethyl taurate/VP copolymer Styrene/    0-1 0.01-1 Acrylates copolymer Xanthan    0-1  0.01-1 Gum EDTA  0.01-0.01 0.01-0.01  0.01-1  0.01-1  0.01-1 Preservative  0.02-2  0.02-2  0.02-2 0.02-2  0.02-2 Titanium    0-10  0.01-10  0.01-10  0.01-10  0.01-10oxide Colorant/    0-5    0-5    0-5    0-5    0-5 Pigment Triethanol   0-3  0.01-3  0.01-3  0.01-3  0.01-3 amine/ Sodium Hydroxide/potassium Hydroxide Stearic acid    0-5  0.01-5  0.01-5  0.01-5  0.01-5Isopropyl    0-10  0.01-10 Myristate Capric/    0-10  0.01-10 CaprylicTriglyceride C12-C15    0-10  0.01-10 alkyl benzoate Mineral oil    0-10 0.01-10 Glyceryl    0-5  0.01-5 stearate Steareth-2    0-5  0.01-5 0.01-5 Steareth-21    0-5  0.01-5 Peg100    0-5  0.01-2  0.01-5Stearate Potassium    0-5  0.01-2 Cetyl Phosphate Tween20    0-5  0.01-5Cetyl    0-4  0.01-4  0.01-4 alcohol Dicaprylyl    0-5  0.01-5 carbonateEthyl hexyl    0-6  0.01-6 methoxy- cinnamate Butyl    0-3  0.01-3 0.01-3  0.01-3 Methoxy- dibenzoyl- methane Ensulizole    0-4  0.01-4Octinoxate    0-7.5 Octisalate    0-5  0.01-5  0.01-5 Octocrylene   0-10  0.01-10  0.01-10 Homosalate    0-10  0.01-10 Dimethicone   0-10  0.01-10  0.01-10 Cyclo-    0-15  0.01-15 methicone Niacinamide   0-5    0-5    0-5    0-5    0-5 Fragrance    0-2    0-2    0-2    0-2   0-2 Glutamine/  0.01-10  0.01-10  0.01-10  0.01-10 Sodium PCA Glycine 0.01-10  0.01-10  0.01-10  0.01-10 Cystine 0.001-2 0.001-2 0.001-20.001-2 0.001-2 4-hexyl- 0.001-3 0.001-3 resorcinol 4-ethyl- 0.001-30.001-3 resorcinol 4-butyl- 0.001-3 resorcinol 4-(1- 0.001-3phenylethyl) resorcinol

TABLE II Water-in-oil topical lotions or creams WO-1 WO-2 WO-3 WO-4Water To 100 To 100 To 100 To 100 Glycerine    0-70    1-70    1-70Propylene glycol    0-5  0.01-5 Butylene glycol    0-5  0.01-5  0.01-5Disteardimonium  0.01-1  0.01-1 Hectorite EDTA  0.01-.01  0.01-1  0.01-1 0.01-1 Preservative  0.02-2  0.02-2  0.02-2  0.02-2 TiO2    0-10 0.01-10  0.01-10  0.01-10 Colorant/pigment    0-5    0-5    0-5    0-5TEA/Sodium    0-3  0.01-3  0.01-3  0.01-3 Hydroxide/potassium HydroxideStearic acid    0-5  0.01-5 Isopropyl Myristate    0-10 Capric/Caprylic   0-10  0.01-10 Triglyceride C12-C15 alkyl benzoate    0-10  0.01-10Mineral oil    0-10 Glyceryl stearate    0-5 Dimethicone copolyol    0-5 0.01-5  0.01-5 Cetyl PEG/PPG-10/1    0-5  0.01-5 Dimethicone Steareth-2   0-2 Sucrose Distearate    0-2  0.01-2 Cetyl alcohol    0-2  0.01-2 0.01-2 Ethyl hexyl    0-6  0.01-6 methoxycinnamate Butyl Methoxy-   0-3  0.01-3  0.01-3  0.01-3 dibenzoylmethane Ensulizole    0-4 0.01-4 Octinoxate    0-7.5 Octisalate    0-5  0.01-5  0.01-5Octocrylene    0-10  0.01-10  0.01-10 Homosalate    0-10  0.01-10Dimethicone    0-10  0.01-10  0.01-10 Cyclomethicone    0-40  0.01-40 0.01-10 Caprylyl methicone    0-10  0.01-10  0.01-10 Dimethicone   0-90  0.01-90  0.01-90 crosspolymer C30-C45 alkyl cetearyl  0.01-90dimethicone crosspolymer Glycolic acid    0-10  0.01-10 KCl    0-5 0.01-5  0.01-5  0.01-5 Iacinamide    0-5  0.01-5  0.01-5  0.01-5Fragrance    0-2    0-2    0-2    0-2 Glutamine/Sodium PCA  0.01-10 0.01-10  0.01-10  0.01-10 Glycine  0.01-10  0.01-10  0.01-10 Cystine0.001-2 0.001-2 0.001-2 0.001-2 4-hexylresorcinol 0.001-34-ethylresorcinol 0.001-3 4-butylresorcinol 0.001-3 4-(1-phenylethyl)0.001-3 resorcinol

TABLE III Vanishing Creams VC-1 VC-2 VC-3 VC-4 Water To 100 To 100 To100 To 100 Glycerine    0-5  0.01-5  0.01-5 EDTA  0.01-.01  0.01-.01 0.01-.01  0.01-.01 Preservative  0.02-2  0.02-2  0.02-2  0.02-2 TiO2 0.01-10  0.01-10  0.01-10  0.01-10 Colorant/pigment    0-5  0.01-5 0.01-5 TEA/Sodium    0-3  0.01-3  0.01-3  0.01-3 Hydroxide/potassiumHydroxide Stearic acid    0-30  0.01-30  0.01-30  0.01-30 IsopropylMyristate    0-5  0.01-10  0.01-10 C12-C15 alkyl benzoate    0-5 0.01-10 Brij 35    0-5  0.01-5 Tween40    0-5  0.01-5 Cetyl alcohol   0-2  0.01-2  0.01-2 Ethyl hexyl    0-6  0.01-6  0.01-6methoxycinnamate Butyl Methoxy-    0-3  0.01-3  0.01-3  0.01-3dibenzoylmethane Ensulizole    0-4  0.01-4 Octisalate    0-5  0.01-5Octocrylene    0-10  0.01-10  0.01-10 Dimethicone    0-5  0.01-5Cyclomethicone    0-5  0.01-5 Dimethicone    0-4  0.01-4 crosspolymerNiacinamide    0-5  0.01-5  0.01-5  0.01-5 Hydroxystearic acid    0-5 0.01-5  0.01-5  0.01-5 Fragrance    0-2    0-2    0-2    0-2Glutamine/Sodium PCA  0.01-10  0.01-10  0.01-10  0.01-10 Glycine 0.01-10  0.01-10  0.01-10 Cystine 0.001-2 0.001-2 0.001-2 0.001-24-hexylresorcinol 0.001-3 4-ethylresorcinol 0.001-3 4-butylresorcinol0.001-3 4-(1-phenylethyl) 0.001-3 resorcinol

1.-15. (canceled)
 16. A personal care composition comprising: a.glutathione precursor comprising, by weight of the composition: i. fromabout 0.001% to about 2% of cystine; ii. optionally, from about 0.01 toabout 10% of glycine; iii. from about 0.01 to about 10% of pyroglutamicacid or a salt or ester thereof; and iv. from about 0.001 to about 3% ofa resorcinol selected from 4-hexylresorcinol, 4-ethylresorcinol, and4-isopropylresorcinol; b. from about 0.005% to about 2% of a retinoid;and c. a cosmetically acceptable carrier; wherein the pH of thecomposition is in the range of from about 3.5 to about 8.5.
 17. Thecomposition of claim 16, wherein the composition is in the form of awater-in-oil emulsion comprising cystine in an aqueous phase, wherein90% of the water droplets have a diameter within the size range of from100 nm to 20 microns.
 18. The composition of claim 16, wherein theretinoid is selected from retinol, retinol esters, retinal, retinoicacid and derivatives and mixtures thereof.
 19. The composition of claim18, wherein retinol esters are selected from retinyl palmitate, retinylacetate, retinyl propionate and mixtures thereof.
 20. The composition ofclaim 16, wherein the composition is a leave-on non-solid skin cosmeticcomposition.
 21. The composition of claim 16, wherein the composition isa vanishing cream.
 22. The composition of claim 16, wherein thecomposition further comprises a nicotinamide compound.
 23. A method forimproving the appearance of skin comprising applying to the skin thecomposition of claim
 16. 24. A personal care composition comprising: a.glutathione precursor comprising, by weight of the composition: i. fromabout 0.0001% to about 2% of cystine; ii. from about 0.01% to about 10%of glycine; and iii. from about 0.001% to about 3% of 4-hexylresorcinol;b. from about 0.0001% to about 10% of at least one vitamin; and c. acosmetically acceptable carrier; wherein the pH of the composition is inthe range of from about 3.5 to about 8.5.
 25. The composition accordingto claim 24, wherein the vitamin is selected from Vitamin A, Vitamin B2,Vitamin B3, Vitamin B6, Vitamin B12, Vitamin C, Vitamin D, Vitamin E,Vitamin K and derivatives and mixtures thereof.
 26. The composition ofclaim 24, wherein the composition is a leave-on non-solid skin cosmeticcomposition.
 27. The composition of claim 24, wherein the composition isa vanishing cream.
 28. The composition of claim 24, wherein thecomposition further comprises a nicotinamide compound.
 29. A method forimproving the appearance of skin comprising applying to the skin thecomposition of claim 24.